Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objective: Primary Outcome/Efficacy Variable(s):

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: /161 (OKAH-161) Title: A controlled clinical study to assess the immunogenicity and reactogenicity of SmithKline Beecham Biologicals varicella vaccine in children aged between 1 and 12 years with a known history of neurodermatitis. SmithKline Beecham Biologicals is currently GlaxoSmithKline Biologicals. Rationale: To examine the safety and immunogenicity of varicella vaccine in subjects with neurodermatitis. Phase: IV Study Period: 31 May 1999 to 21 August 2002 Study Design: Controlled, prospective, randomised, open clinical study with 2 parallel groups. Centres: Thirteen centres in Germany Indication: Children aged 1 to 12 years with a history of neurodermatitis. Treatment: The study groups were as follows: Group VAR-1Y received varicella vaccination in the 1st study year, Group VAR-2Y received varicella vaccination in the 2nd study year. Subjects in both groups received varicella vaccine subcutaneously in the left upper arm (for left-handers, in the right upper arm) as a single dose. Objective: To assess the safety of the varicella vaccine based on detailed diary cards completed by the vaccinee or his/her guardian(s) to collect information on local and general symptoms. Primary Outcome/Efficacy Variable(s): Individual differences in changes from baseline in the SCORAD* indices at the follow-ups after 8 weeks in the 1 st year of observation, which were to be compared between the VAR-1Y group and the VAR-2Y group. * SCORAD score was the severity grading in accordance with the guidelines of the European Working Group Atopic Eczema. Secondary Outcome/Efficacy Variable(s): Other SCORAD index calculations Seroconversion rates (defined as the percentage of subjects with varicella zoster virus (VZV)-specific antibody increase from titre <4 pre-vaccination to >4 post-vaccination) at week 8 and again at month 12 after vaccination, Occurrence, intensity, and duration of solicited local symptoms within 7 days (Day 0-6) following vaccination, Occurrence of any and Grade 3 fever, and relationship to vaccination, within 7 days (Day 0-6) ;following vaccination, Occurrence of any and Grade 3 rash, and relationship to vaccination, within 70 days (Day 0 69) following vaccination, Occurrence of unsolicited adverse events (AEs) within 70 days (Day 0 69) following vaccination, Occurrence of serious adverse events (SAEs) throughout the study period. Statistical Methods: The analyses were performed on the Total Cohort, on the According-To-Protocol (ATP) Cohort for Immunogenicity, on the ATP Cohort for the analysis of SCORAD Index and on the ATP Cohort for Safety - The Total cohort included all subjects enrolled in the study, - The ATP cohort for safety included all subjects who received the vaccine dose, - The ATP cohort for the analysis of SCORAD index included all subjects who received the vaccine dose and were initially seropositive or had initially unknown antibody status (for VAR-1Y group only) for whom SCORAD index data were available, and who complied with the eligibility criteria as defined in the protocol, - The ATP cohort for immunogenicity included all subjects who received the vaccine dose and complied with the procedures defined in the protocol and for whom immunogenicity data were available. Analysis of immunogenicity: The analysis of immunogenicity was performed on the ATP Cohort for Immunogenicity. Geometric mean titres (GMTs) and seroconversion rates of VZV-specific antibody titres were summarised at each blood sampling time point with 95% confidence interval (CI). Analysis of safety: The analysis of safety was performed on the ATP Cohort for the analysis of SCORAD Index. The SCORAD index was calculated from the following items at each visit: A: Extent (age-dependent)

2 All body areas are assigned numbers. These numbers were added according to areas affected. RULE OF NINES: Body area Children > 2 years Children < 2 years Head: Face Back of the head Trunk: Chest/abdomen Back/buttocks Extremities: Front side of leg 9 6 Back side of leg 9 6 Front side of arm Back side of arm Hand 1 - Genitals: 1 - B: Intensity Criteria Intensity Erythema Edema/papules or infiltration Exudation/crusting Excoriation See below Lichenification Dryness Total Intensity was assessed according to the following scale: 0 = absent; 1 = mild; 2 = moderate; 3 = pronounced. All points were added. C: Subjective Symptoms The subjective health condition (itching and insomnia) was documented using a visual analog scale ranging from 0 to 10 points. Itching: 0 = no itching,..., 10 = most severe itching Sleep loss: 0 = normal sleeping behavior,..., 10 = sleeplessness The SCORAD index was calculated according to the following formula: A/5 + 7xB/2 + C = SCORAD index (maximum 103) This was an equivalence study. The null hypothesis was that there were medically relevant differences in the SCORAD index among unvaccinated and vaccinated children with a known history of neurodermatitis. This hypothesis was to be rejected by this study. SCORAD index and the difference of the SCORAD index with the baseline were summarised at the follow-up after 8 weeks in the 1 st year of observation for each group. The test of equivalence used a one-sided 95% CI for the difference between the 2 groups regarding the individual differences in changes from baseline in the SCORAD indices at the followups after 8 weeks in the 1 st year of observation. The equivalence was proven if the upper limit of the CI of the test was below The analysis of safety was also performed on the ATP Cohort for Safety. For each solicited symptom, the percentage of subjects with solicited local and general symptom was summarised during the 7-day (Day 0 6) follow-up period. The percentage of subjects reporting unsolicited AEs within 70 days (Day 0 69) following vaccination was tabulated for each group according to the World Health Organisation (WHO) preferred term. The occurrence of SAEs throughout the entire study period was tabulated for each group according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Study Population: Children 1-12 years of age with chronic neurodermatitis for at least 1 year, in good physical condition on inclusion in the study as verified by medical history and physical examination. Children with previous varicella infection or VZV vaccination, presence of neurodermatitis with a severity grade of a SCORAD index >40, vaccination with a live vaccine within one month prior to inclusion in the study (e.g. rubella, measles, mumps, oral polio vaccine) and planned vaccine administration until the completion of the study after 8 weeks were excluded from the study. Written informed consent was obtained from the parents/guardians of the subjects prior to entry into the study. Number of Subjects: VAR-1Y VAR-2Y Planned, N Randomised, N (Total Cohort) Completed, n (%) 66 (82.5) 45 (56.2) Total Number Subjects Withdrawn, n (%) 14 (17.5) 35 (43.8) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0)

3 Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Withdrawn for other reasons, n (%) 14 (17.5) 35 (43.8) Demographics VAR-1Y VAR-2Y N (Total Cohort) Females: Males 41:39 42:38 Mean Age, years (SD) 3.3 (1.5) 3.1 (1.8) White/Caucasian, n (%) 79 (98.8) 75 (93.8) Primary Efficacy Results: Difference of the SCORAD index between Week 8 and baseline (before vaccine administration) at 1 st year of observation between the 2 groups (ATP Cohort for the Analysis of SCORAD Index) Group LSmean SD 90%CI LL UL Difference VAR-1Y VAR- 2Y * LSmean: least square mean 90%CI: 90% confidence interval; LL, UL: lower limit, upper limit * As the UL was below 10.0, the equivalence between the two groups was shown. Secondary Outcome Variable(s): Total SCORAD index and difference with baseline (before vaccine administration) (ATP Cohort for the Analysis of SCORAD Index) Group Time point N SCORAD index Mean SD VAR-1Y 1 st year Week st year Day st year Week st year Month nd year Month VAR-2Y 1 st year Week st year Week st year Month nd year Day nd year Week nd year Month N: number of subjects with symptom sheets completed, SD: standard deviation Secondary Outcome Variable(s): Seroconversion rate and GMTs of varicella-specific antibody titres for both groups (ATP Cohort for Immunogenicity) Time points N GMT Seroconversion rate Value 95%CI n % 95%CI LL UL LL UL Week ( 4) NA NA Week Month N: number of subjects with available results n (%): number (percentage) of seropositive subjects NA: not applicable 95%CI: 95% confidence interval; LL, UL: lower limit, upper limit Number and percentage of subjects with solicited local symptoms during the 7-day (Day 0 6) follow-up period after vaccination (ATP Cohort for Safety) Symptom Intensity VAR-1Y (N = 70) VAR-2Y (N = 47) n % n % Redness Any >20 mm Swelling Any >20 mm

4 Soreness/ Pain at Any injection site Grade N: number of subjects with a symptom sheet completed n (%): number (percentage) of subjects with a specific symptom Any: incidence of a particular symptom regardless of grade Grade 3 soreness: symptom which prevented normal everyday activities Duration of solicited local symptoms after vaccination (ATP Cohort for Safety) Symptom VAR-1Y (N = 70) VAR-2Y (N = 47) N Mean SD N Mean SD Redness Swelling Soreness N: number of subjects with available results n: number of subjects with the symptom Mean: duration (average) in days SD: standard deviation Number and percentage of subjects reporting solicited general symptoms during the 7-day (Day 0 6) follow-up period after vaccination (ATP Cohort for Safety) Symptom Fever (Rectal temperature) Intensity/ Relationship VAR-1Y (N = 70) VAR-2Y (N = 47) n % n % 38.0 C Related Rash* Any Grade Related N: number of subjects with a symptom sheet completed n (%): number (percentage) of subjects with a specific symptom Any: incidence of a particular symptom regardless of grade or relationship to vaccination Grade 3: prevented normal everyday activities Related: solicited symptom considered by the investigator to have a causal relationship to study vaccination * Rash was documented over the 70 days (Day 0 69) after vaccination Safety Results: Number (%) of subjects with unsolicited adverse events (AEs) (ATP Cohort for Safety) Most frequent adverse events - On-Therapy- (occurring within Day 0 69 following vaccination) VAR-1Y (N = 70) VAR-2Y (N = 47) Subjects with any AE(s), n (%) 32 (45.7) 9 (19.1) Rhinitis 7 (10.0) 1 (2.1) Upper respiratory tract infection 7 (10.0) 1 (2.1) Coughing 6 (8.6) 0 (0.0) Bronchitis 3 (4.3) 1 (2.1) Ear disorder, not otherwise specified (NOS) 3 (4.3) 1 (2.1) Otitis media 3 (4.3) 1 (2.1) Fatigue 3 (4.3) 0 (0.0) Infection 3 (4.3) 0 (0.0) Other events 2 (2.9) 1 (2.1) Pneumonia 2 (2.9) 1 (2.1) Diarrhoea 2 (2.9) 0 (0.0) Gastroenteritis 2 (2.9) 0 (0.0) Infection, fungal 2 (2.9) 0 (0.0) Laryngitis 0 (0.0) 2 (4.3) Arthralgia 0 (0.0) 1 (2.1) Asthma 0 (0.0) 1 (2.1) Infection, bacterial 0 (0.0) 1 (2.1) Safety Results: Number (%) of subjects with serious adverse events (SAEs) (Total Cohort)

5 Serious adverse events, n (%) [n considered by the investigator to be related to study medication] All SAEs VAR-1Y VAR-2Y Subjects with any SAE(s), n (%)[related] 6 (7.5) [0] 0 (0.0) [0] Appendicitis 1 (1.3) [0] 0 (0.0) [0] Bronchitis acute, NOS 1 (1.3) [0] 0 (0.0) [0] Dermatitis atopic 1 (1.3) [0] 0 (0.0) [0] Ear disorder, NOS 1 (1.3) [0] 0 (0.0) [0] Eczema 1 (1.3) [0] 0 (0.0) [0] Hydrocele, phimosis 1 (1.3) [0] 0 (0.0) [0] Fatal SAEs Var-1Y Var-2Y Subjects with fatal SAEs, n (%) [related] 0 (0.0) [0] 0 (0.0) [0] Conclusions: Please refer to publications section. Date updated: 21-August-2015